Interferon is an important cytokine which has multiple effects on the immune response (Theofilopoulos et al., Annu. Rev. Immunol., 23:307-336, 2005). Interferons include type 1 interferons (e.g., interferon-alpha (IFN-α) and interferon-beta (IFN-β)) and type 2 interferons (e.g., interferon-gamma (IFN-γ)). All type 1 IFNs are recognized by a shared receptor (IFN-αR) composed of two transmembrane proteins, IFN-αR1 and IFN-αR2. IFN-α's are known to inhibit angiogenesis (Sidky Y A and E C Borden, Cancer Res., 47:5155, 1987), mediate stimulation and differentiation of dendritic cells (Santini et al., J Exp Med, 191:1777, 2000), and are important in in vivo proliferation, expansion and long-term survival of antigen specific CD8+ T cells (Tough D F et al., Science, 272:1947, 1996). Although first described for their ability to inhibit viral replication, IFN-α's have multiple properties exhibiting antiproliferative effects, induction of apoptosis (Rodriguez-Villanueva J and T J McDonnell, Int J Cancer, 61:110, 1995) and induction of the tumor suppressor gene, P53, in tumor cells (Takaoka A et al., Nature, 424:516, 2003). Thus, IFN-α's were the first recombinant proteins used for the treatment of various cancers.
Unfortunately, the use of IFN-α to treat cancer has been limited by its short half-life and associated systemic toxicities (Weiss K, Semin Oncol, 25:9, 1998; Jones G J and Itri L M, Cancer, 57:1709, 2006). Because of the short in vivo half-life of IFN-α, frequent administration is required. Pharmacokinetic (PK) studies have indicated that only 0.01% of subcutaneously injected IFN-α reaches the target tumor site (Suzuki K et al., Gene Ther., 10(9):765-773, 2003). The most common adverse events associated with IFN-α therapy are flu-like symptoms, fatigue, anorexia, and central nervous system and psychiatric reactions, and some of these side-effects may become dose-limiting (Jones G J and Itri L M, Cancer, 57:1709, 2006). Given these limitations, it is difficult to achieve effective IFN-α concentrations at sites of malignant disease without causing systemic toxicity. The limitations of systemic IFN-α therapy have led to the exploration of alternative strategies to deliver IFN-α safely and effectively into the tumor vicinity.